Silvan Licher

Serum magnesium is associated with the risk of dementia

Objective: To determine if serum magnesium levels are associated with the risk of all-cause dementia and Alzheimer disease. Methods: Within the prospective population-based Rotterdam Study, we measured serum magnesium levels in 9,569 participants, free from dementia at baseline (1997–2008). Participants were subsequently followed up for incident dementia, determined according to the DSM-III-R criteria, until January 1, 2015. We used Cox proportional hazard regression models to associate quintiles of serum magnesium with incident all-cause dementia. We used the third quintile as a reference group and adjusted for age, sex, Rotterdam Study cohort, educational level, cardiovascular risk factors, kidney function, comorbidities, other electrolytes, and diuretic use. Results: Our study population had a mean age of 64.9 years and 56.6% were women. During a median follow-up of 7.8 years, 823 participants were diagnosed with all-cause dementia. Both low serum magnesium levels (≤0.79 mmol/L) and high serum magnesium levels (≥0.90 mmol/L) were associated with an increased risk of dementia (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.02–1.69, and HR 1.30, 95% CI 1.02–1.67, respectively). Conclusions: Both low and high serum magnesium levels are associated with an increased risk of all-cause dementia. Our results warrant replication in other population-based studies.

Vitamin D and the Risk of Dementia: The Rotterdam Study

BACKGROUNDnVitamin D has gained interest as a potentially modifiable risk factor for dementia because of its putative neuroprotective effects. However, longitudinal studies examining the association between vitamin D and dementia have provided inconsistent results.nnnOBJECTIVEnTo determine the relationship of serum vitamin D with prevalent and incident dementia in the general population.nnnMETHODSnWithin the prospective Rotterdam Study, we measured serum 25-hydroxyvitamin D concentrations between 1997 and 2001 using electrochemiluminescence-immunoassay in 6220 participants 55 years or older. We assessed dementia at baseline and continuously during follow-up until 1 January 2015. We used appropriate regression models to determine the relationship of vitamin D with prevalent and incident dementia, including Alzheimers disease (AD). We adjusted models for age, sex, and season of blood collection. Additionally, we adjusted for ethnicity, education, cardiovascular risk factors, serum calcium, kidney function, depression, outdoor-activity and APOEɛ4 carriership.nnnRESULTSnAt baseline, 127 of 6,220 participants had dementia, of whom 97 had AD. Lower vitamin D concentrations were associated with a non-significantly higher prevalence of dementia (adjusted OR, per SD decrease 1.20, 95% CI 0.95;1.52), but not with AD (adjusted OR: 0.97, 95% CI 0.74;1.29). Among 6,087 non-demented participants with 68,884 person-years of follow-up, 795 participants developed dementia, of whom 641 had AD. Lower vitamin D concentrations were associated with higher risk of dementia (adjusted HR, per SD decrease 1.11, 95% CI 1.02;1.20) and AD (adjusted HR: 1.13, 95% CI 1.03;1.24).nnnCONCLUSIONnLower serum vitamin D concentrations are associated with a higher incidence of dementia.

Subregional volumes of the hippocampus in relation to cognitive function and risk of dementia

Background Total hippocampal volume has been consistently linked to cognitive function and dementia. Yet, given its complex and parcellated internal structure, the role of subregions of the hippocampus in cognition and risk of dementia remains relatively underexplored. We studied subregions of the hippocampus in a large population‐based cohort to further understand their role in cognitive impairment and dementia risk. Methods We studied 5035 dementia‐ and stroke‐free persons from the Rotterdam Study, aged over 45 years. All participants underwent magnetic resonance imaging (1.5 T) between 2005 and 2015. Automatic segmentation of the hippocampus and 12 of its subregions was performed using the FreeSurfer software (version 6.0). A cognitive test battery was performed, and participants were followed up for the development of dementia until 2015. Associations of hippocampal subregion volumes with cognition and incident dementia were examined using linear and Cox regression models, respectively. All analyses were adjusted for age, sex, education, and total hippocampal volume. Results Mean age was 64.3 years (SD 10.6) with 56% women. Smaller volumes of the hippocampal fimbria, presubiculum and subiculum showed the strongest associations with poor performance on several cognitive domains, including executive function but not memory. During a mean follow‐up of 5.5 years, 76 persons developed dementia. Smaller subiculum volume was associated with risk of dementia adjusted for total volume (hazard ratio per SD decrease in volume: 1.75, 95% confidence interval 1.35; 2.26). Conclusions In a community‐dwelling non‐demented population, we describe patterns of association between hippocampal subregions with cognition and risk of dementia. Specifically, the subiculum was associated with both poorer cognition and higher risk of dementia. HighlightsHippocampal subregions were related to many cognitive domains.The subiculum and pre‐subiculum displayed strong relations to executive dysfunction.Smaller subiculum volume was associated to risk of incident dementia.The subiculum relation to dementia risk remained stable over the follow‐up period.

Association of Retinal Neurodegeneration on Optical Coherence Tomography With Dementia: A Population-Based Study

Importance Retinal structures may serve as a biomarker for dementia, but longitudinal studies examining this link are lacking. Objective To investigate the association of inner retinal layer thickness with prevalent and incident dementia in a general population of Dutch adults. Design, Setting, and Participants From September 2007 to June 2012, participants from the prospective population-based Rotterdam Study who were 45 years and older and had gradable retinal optical coherence tomography images and at baseline were free from stroke, Parkinson disease, multiple sclerosis, glaucoma, macular degeneration, retinopathy, myopia, hyperopia, and optic disc pathology were included. They were followed up until January 1, 2015, for the onset of dementia. Exposures Inner retinal layer thicknesses (ie, retinal nerve fiber layer [RNFL]) and ganglion cell–inner plexiform layer (GC-IPL) thicknesses measured on optical coherence tomography images. Main Outcomes and Measures Odds ratios and hazard ratios for incident dementia per SD decrease in retinal layer thickness adjusted for age, sex, education, and cardiovascular risk factors. Results Of 5065 individuals eligible for optical coherence tomography scanning, 3289 (64.9%) (mean [SD] age 68.9 [9.9] years, 1879 [57%] women) were included in the analysis. Of these 3289 individuals, 41 (1.2%) already had dementia. Thinner GC-IPL was associated with prevalent dementia (odds ratio per SD decrease in GC-IPL, 1.37 [95% CI, 0.99-1.90]). No association was found of RNFL with prevalent dementia. During 14 674 person-years of follow-up (mean [SD], 4.5 [1.6] years), 86 individuals (2.6%) developed dementia of whom 68 (2.1%) had Alzheimer disease. Thinner RNFL at baseline was associated with an increased risk of developing dementia (hazard ratio per SD decrease in RNFL, 1.44 [95% CI, 1.19-1.75]), which was similar for Alzheimer disease (hazard ratio, 1.43 [95% CI, 1.15-1.78]). No association was found between GC-IPL thickness and incident dementia (hazard ratio, 1.13 [95% CI, 0.90-1.43]). Conclusions and Relevance Thinner RNFL is associated with an increased risk of dementia, including Alzheimer disease, suggesting that retinal neurodegeneration may serve as a preclinical biomarker for dementia.

External validation of four dementia prediction models for use in the general community-dwelling population: a comparative analysis from the Rotterdam Study

To systematically review the literature for dementia prediction models for use in the general population and externally validate their performance in a head-to-head comparison. We selected four prediction models for validation: CAIDE, BDSI, ANU-ADRI and DRS. From the Rotterdam Study, 6667 non-demented individuals aged 55xa0years and older were assessed between 1997 and 2001. Subsequently, participants were followed for dementia until 1 January, 2015. For each individual, we computed the risk of dementia using the reported scores from each prediction model. We used the C-statistic and calibration plots to assess the performance of each model to predict 10-year risk of all-cause dementia. For comparisons, we also evaluated discriminative accuracy using only the age component of these risk scores for each model separately. During 75,581 person-years of follow-up, 867 participants developed dementia. C-statistics for 10-year dementia risk prediction were 0.55 (95% CI 0.53–0.58) for CAIDE, 0.78 (0.76–0.81) for BDSI, 0.75 (0.74–0.77) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS. Calibration plots showed that predicted risks were too extreme with underestimation at low risk and overestimation at high risk. Importantly, in all models age alone already showed nearly identical discriminative accuracy as the full model (C-statistics: 0.55 (0.53–0.58) for CAIDE, 0.81 (0.78–0.83) for BDSI, 0.77 (0.75–0.79) for ANU-ADRI, and 0.81 (0.78–0.83) for DRS). In this study, we found high variability in discriminative ability for predicting dementia in an elderly, community-dwelling population. All models showed similar discriminative ability when compared to prediction based on age alone. These findings highlight the urgent need for updated or new models to predict dementia risk in the general population.

Lifetime risk of common neurological diseases in the elderly population

Objective To quantify the burden of common neurological disease in older adults in terms of lifetime risks, including their co-occurrence and preventive potential, within a competing risk framework. Methods Within the prospective population-based Rotterdam Study, we studied lifetime risk of dementia, stroke and parkinsonism between 1990 and 2016. Among 12u2009102 individuals (57.7% women) aged ≥45 years free from these diseases at baseline, we studied co-occurrence, and quantified the combined, and disease-specific remaining lifetime risk of these diseases at various ages for men and women separately. We also projected effects on lifetime risk of hypothetical preventive strategies that delay disease onset by 1, 2 and 3u2009years, respectively. Results During follow-up of up to 26 years (156u2009088 person-years of follow-up), 1489 individuals were diagnosed with dementia, 1285 with stroke and 263 with parkinsonism. Of these individuals, 438 (14.6%) were diagnosed with multiple diseases. Women were almost twice as likely as men to be diagnosed with both stroke and dementia during their lifetime. The lifetime risk for any of these diseases at age 45 was 48.2% (95% CI 47.1% to 51.5%) in women and 36.2% (35.1% to 39.3%) in men. This difference was driven by a higher risk of dementia as the first manifesting disease in women than in men (25.9% vs 13.7%; p<0.001), while this was similar for stroke (19.0%vs18.9% in men) and parkinsonism (3.3% vs 3.6% in men). Preventive strategies that delay disease onset with 1 to 3u2009years could theoretically reduce lifetime risk for developing any of these diseases by 20%–50%. Conclusion One in two women and one in three men will develop dementia, stroke or parkinsonism during their life. These findings strengthen the call for prioritising the focus on preventive interventions at population level which could substantially reduce the burden of common neurological diseases in the ageing population.

Cognitive Impairment, Sexual Activity and Physical Tenderness in Community-Dwelling Older Adults: A Cross-Sectional Exploration

Background: The ability to engage in sexual activity and better cognitive functioning are both associated with better health. However, the association between cognitive functioning and sexual activity is understudied. Objective: To examine the association between cognitive functioning with sexual activity and physical tenderness among community-dwelling older adults. Methods: From the Rotterdam Study, cognitive impairment and sexual activity were assessed in 4,201 community-dwelling, 60+ year olds between 2008 and 2014 in the Netherlands. Mild cognitive impairment (MCI) was based upon subjective complaints related to age and education-adjusted test scores. Mini-Mental State Examination (MMSE) impairment was defined by a score of < 26. Sexual activity and physical tenderness (e.g., fondling or kissing) in the last 6 months were assessed at an interview. Analyses were stratified by gender and partner status, with prevalence rates for the “no impairment” categories weighted based on age from the cognitive impairment categories. Inter-rater reliability was examined utilising 74 cohabiting couples of opposite gender. Results: It was found that 14% were categorised as having cognitive impairment, and < 1% as dementia (excluded from subsequent analyses). There was strong evidence that the odds of engaging in physical tenderness (observed through MMSE < 26, OR 2.14, 95% CI 1.32–3.48, p = 0.002) and sexual activity (MCI, OR 2.36, 95% CI 1.35–4.12, p = 0.003) among partnered females with no impairment was twice that observed among cognitively impaired partnered females. There was weak evidence that the odds of engaging in physical tenderness (MMSE < 26, OR 1.59, 95% CI 1.04–2.42, p = 0.03) and sexual activity (MMSE < 26, OR 1.51, 95% CI 1.02–2.24, p = 0.04) among partnered males with no impairment was 50% greater than observed among cognitively impaired partnered males. The associations between cognitive functioning and physical tenderness continued to remain after adjustment for physical function, diabetes, cardiovascular disease and cancer. There was no clear evidence of a difference between amnestic and non-amnestic MCI for sexual behaviour. There was moderate to substantial agreement among the coupled adults who had 1 partner categorised with MCI. Conclusion: Having no cognitive impairment was associated with more engagement in sexual activity and physical tenderness among community-dwelling older adults. Sexuality is an important aspect of active aging and our findings illustrate a potential barrier to maintaining or instigating intimate relationships as we age. Longitudinal analyses are required to explore the direction of effect.

EXTERNAL VALIDATION OF FIVE MODELS FOR PREDICTING DEMENTIA IN THE GENERAL COMMUNITY-DWELLING POPULATION: RESULTS FROM THE PROSPECTIVE POPULATION-BASED ROTTERDAM STUDY

cognitive function as the outcome with time-varying separate indicators for having elective or nonelective hospitalizations, and their interactions with time. Results:Of the 930 participants, 613 were hospitalized at least once over an average of 4.8 (SD1⁄42.6) years of follow-up; 260 (28.0%) had at least one elective hospital admission, and 553 (59.5%) had at least one nonelective hospital admission. Two hundred participants (21.5%) had both an elective and nonelective hospitalization. In separate models adjusted for age at baseline, sex, education, and self-reported chronic medical conditions, the rate of cognitive decline accelerated (as compared to rate of change with no hospitalization) after elective hospitalizations (estimate1⁄4 -0.025, p<0.001) and the acceleration was almost twice as fast after nonelective hospitalizations (estimate 1⁄4 -0.043, P<0.001). When both types of hospitalizations were put in the same model, nonelective hospitalizations were related to faster cognitive decline (estimate1⁄4 -0.042, p<0.001) but the association for elective hospitalizations was markedly attenuated and not significant (estimate1⁄4 -0.002, p1⁄40.81). Inferences were essentially unchanged after adding terms for mean length of stay, surgeries, ICU stays, and Charlson comorbidity index, a measure of seriousness of illness. Conclusions:These data indicate that elective hospitalizations are not significantly related to acceleration in cognitive decline in older persons after accounting for nonelective hospitalizations.

RETINAL NEURODEGENERATION ON OPTICAL COHERENCE TOMOGRAPHY AND RISK OF DEMENTIA AND STROKE

APL1b28 peptide in plasma. The concentration of APL1b28 is w0.4pM, which is much less than that in CSF (w500pM). Currently, we are analyzing the APL1b28 ratio in CSF and plasma paired samples. We are also investigating correlation between plasma APL1b28 ratio and CSF Ab42 ratio. Conclusions:We have tried to develop an Ab42 surrogate marker in peripheral blood. We intend to show how and to what degree the plasma APL1b28 ratio correlates with CSF Ab42 ratio.